2-arylalkylthio -imidazoles, 2-arylalkenyl -thio -imidazoles and 2-arylalkinyl -thio -imidazoles as anti -inflammatory substances and substances inhibiting the release of cytokine

ABSTRACT

The invention relates to 4-heteroaryl-5-phenylimidazole derivatives having 2-arylalkylthio, 2-arylalkenylthio and 2-arylalkynylthio substitution, of the general formula I:                    
     in which Ar is a phenyl radical, Het is a hetero aromatic radical, A is an alkylene chain, R 1  is an alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamido or alkylcarbonyl group and R 2  is an alkyl, hydroxyl, alkoxy, alkoxycarbonyl, sulfonamido, carboxyl, nitro or aminocarbonyl group or a halogen atom. n can be 1 or 2 and m is 0 to 2. The compounds according to the invention show antiinflammatory activity.

The present invention relates to 2-arylaklylthioimidazole,2-arylalkenylthioimidazole and 2-arylalkynylthioimidazole derivatives, aprocess for their preparation and medicaments which contain theseimidazole derivatives.

It is known that various imidazole derivatives have an antiinflammatoryactivity. Inter alia, compounds having 4,5-di(hetero)arylimidazolestructural elements have been investigated in detail.

Thus U.S. Pat. No. 5,656,644 and WO 93/14081 disclose4-aryl-5-heteroarylimidazole derivatives which are substituted in the2-position by an optionally substituted aryl or heteroaryl group andwhich have an inhibitory activity on the release of cytokines such asIL-1, IL-6, IL-8 and TNF.

U.S. Pat. No. 3,940,486 discloses 4(5)-phenyl-5(4)-heteroarylimidazolederivatives which are substituted in the 2-position by an alkyl,cycloalkyl or phenyl radical. Various pharmaceutical actions of thesecompounds, such as an antiinflammatory activity, are mentioned.

U.S. Pat. No. 4,585,771 discloses 4,5-diphenylimidazole derivativeswhich are substituted in the 2-position by a pyrrolyl, indolyl,imidazolyl or thiazolyl radical.

These compounds have an antiinflammatory and antiallergic activity.

U.S. Pat. Nos. 4,528,298 and 4,402,960 disclose4,5-di(hetero)arylimidazole derivatives which are substituted in the2-position by a thio, sulfinyl or sulfonyl group having a phenyl,pyridyl, N-oxypyridyl, pyrimidinyl, thiazolyl or thienyl radical. Thesecompounds have an antiinflammatory and antiallergic activity.

U.S. Pat. Nos. 4,461,770 and 4,584,310 disclose4(5)-aryl-5(4)-heteroarylimidazole derivatives which are substituted inthe 2-position by a thio, sulfinyl or sulfonyl group having asubstituted or unsubstituted aliphatic hydrocarbon radical. Thesubstituted or unsubstituted aliphatic hydrocarbon radical is, forexample, a phenyl-C₁₋₄-alkyl group in which the phenyl radical can besubstituted by C₁₋₄-alkyl, C₁₋₄-alkoxy, halogen having an atomic weightof not more than 35, nitro, amino or N,N-di-C₁₋₄-alkylamino. Thesecompounds have, inter alia, an antiinflammatory activity.

4,5-Diaryl-substituted imidazoles as cyclooxygenase-2-inhibitors aredisclosed in WO 95/00501.

The molecular target of the 4-(4-fluorophenyl)-5-(4-pyridyl)imidazolederivatives is described by Wilson K. P. et al. (Chemistry & Biology(1997), 4, 423-431) and Young P. R. et al. (J. Biol. Chem. (1997), 272,12116-12121) as the p38 MAP kinase (mitogen-activatable kinase)activated in the signal transduction of inflammatory stimuli in aphosphorylation cascade, and a serine threonine kinase (Cobb, M. H.,Goldsmith, E. J., J. Biol. Chem. (1995), 270, 14843-14846). According toWilson K. P. et al. and Young P. R. et al., the structural elementcompetes with ATP for binding to the ATP binding site of the kinasecenter (for this cf. Tong et al. & Pargellis, C. A. Nat.Struct. Biol. 4,(1997) 311-316).

Other 1,2-diaryl-substituted heteroaromatic systems additionally show ahigh affinity for enzyme systems of the arachidonic acid cascade, whosemetabolic products exert decisive influence on the inflammatory process.It is seen that with suitable choice of the substituents, of thearomatics flanking the heterocycle, a favorable combination effect takesplace on targets such as 5-lipoxygenase, cyclooxygenase-1 and -2 and p38MAP kinase (TNF-α, IL-1β release).

Despite numerous known compounds, a need furthermore exists forsubstances having antiinflammatory activity, which inhibit the releaseof various cytokines and serve as inhibitors of the mediators of thearachidonic acid cascade. In particular, a need exists for compoundswhich do not only act on the parameters which are decisive in the acutecourse of inflammatory diseases (mediators of inflammation), but whichcan also intervene in the immunological processes crucial to the chroniccourse (cytokine release, expression of cell-surface antigens).

One object of the present invention consists in making such compoundsavailable.

It has now surprisingly been found that 4-heteroaryl-5-phenylimidazolederivatives which are substituted in the 2-position by a phenylalkylthiogroup whose phenyl radical is in turn substituted by an alkylthio,alkylsulfinyl, alkylsulfonyl, sulfonamido or aklycarbonyl group achievethis object.

The present invention thus relates to a compound of the general formulaI:

in which

Ar is a phenyl radical which can optionally be substituted by one ormore substituents, selected from halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy andC₁₋₄-alkylthio;

Het is a pyridyl, pyrimidinyl or pyrazinyl radical which can optionallybe substituted by one or more substituents selected from halogen, amino,C₁₋₄-alkylamino, C₁₋₄-alkyl, hydroxyl, C₁₋₄-alkoxy or C₁₋₄-alkylthio;

A is a straight-chain or branched, saturated or unsaturated alkylenechain having up to 6 carbon atoms;

R¹ is C₁₋₄-alkylthio, C₁₋₄-alkylsulfinyl, C₁₋₄-alkylsulfonyl,sulfonamido or C₁₋₄-alkylcarbonyl;

R² is halogen, C₁₋₄-alkyl, hydroxyl, C₁₋₄-alkoxy, C₁₋₄-alkoxycarbonyl,sulfonamido, carboxyl, nitro or aminocarbonyl;

n is 1 or 2 and

m is 0 to 2

or a pharmaceutically tolerable salt thereof.

“Alkyl” is presently understood as meaning a lower alkyl group having upto 4 C atoms, which can be straight-chain or branched. This includes,for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl andtert-butyl.

“Alkoxy”, “alkylthio”, “alkylamino”, “alkylsulfinyl”, “alkylsulfonyl”,“alkylcarbonyl” and “alkoxycarbonyl” are presently in each caseunderstood as meaning a group which contains an alkyl group definedabove.

“Halogen” is presently understood as meaning fluorine, chlorine, bromineand iodine, preferably fluorine, chlorine and bromine and in particularfluorine.

A “straight-chain or branched, saturated or unsaturated alkylene chainhaving up to 6 carbon atoms” is presently understood as meaning aC₁₋₆-alkylene chain, such as methylene, ethylene, 1,3-propylene,1-methylethylene, 2-methylethylene, 1,4-butylene,1-methyl-1,3-propylene, 2-methyl-1,3-propylene, 3-methyl-1,3-propylene,1-ethylethylene, 2-ethylethylene, 2,3-dimethylethylene and2,2-dimethyl-1,3-propylene, a C₃₋₆-alkenylene chain having one or moredouble bonds, such as propenylene and allenylene, and a C₃₋₆-alkynylenechain having one or more triple bonds, such as propynylene andbutynylene. The straight-chain or branched, saturated or unsaturatedalkylene chain A is preferably a straight-chain, saturated alkylenechain having 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms, namelymethylene or ethylene.

The heteroaromatic radical Het in the compound of the general formula Iis pyridyl, pyrimidinyl or pyrazinyl, where these heteroaromaticradicals can optionally be substituted. The substituent is preferably ahalogen, or an amino group. Particularly preferably, the heteroaromaticradical Het is 4-pyridyl, 3-aminopyridyl, 2,4-pyrimidinyl or3-amino-2,4-pyrimidinyl.

The substituents by which the phenyl radical Ar in the compound of thegeneral formula I can each be substituted are preferably fluorine,chlorine, bromine, C₁₋₄-alkyl, C₁₋₄-alkoxy or C₁₋₄-alkylthio.Particularly advantageously, the phenyl radical Ar is substituted in thepara-position by fluorine, methoxy or methylthio.

The phenyl radical Ar is particularly preferably a 4-fluorophenyl group.

The phenyl group of the phenylalkylthio radical which substitutes theimidazole base unit in the compound of the general formula I in the2-position, is substituted according to the invention by at least onegroup R¹, but at most by two groups R¹. The substituent R¹ is aC₁₋₄-alkylthio, C₁₋₄-alkylsulfinyl, C₁₋₄-alkylsulfonyl, sulfonamido orC₁₋₄-alkylcarbonyl group, where R¹ is advantageously a methylthio,methylsulfinyl, methylsulfonyl, sulfonamido or acetyl group.

The phenyl group of the phenylalkylthio radical which substitutes theimidazole base unit in the compound of the general formula I in the2-position can include further substituents R². These substituents R²are C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-alkoxycarbonyl, sulfonamido, carboxyl,hydroxyl, nitro and aminocarbonyl, and also halogen, such as fluorine,chlorine, bromine and iodine. The phenyl radical in the phenylalkyl sidechain of the compound of the general formula I can have from 0 to 2substituents R², which can be identical or different. Compounds of thegeneral formula I are preferred here in which n is 1 and m is 0-2.

Compounds of the general formula I have proven particularly advantageousin which the phenyl radical Ar is a 4-fluorophenyl group, theheteroaromatic radical Het is a 4-pyridyl, 3-aminopyridyl,2,4-pyrimidinyl or 3-amino-2,4-pyrimidinyl group, A is methylene orethylene, n is 1 and m is 0-2.

The following compounds of the general formula I may be mentioned by wayof example:

5-(4-fluorophenyl)-2-[(4-methylthiophenyl)methylthio]-4-pyridylimidazole

5-(4-fluorophenyl)-2-[(4-methylsulfinylphenyl)methylthio]-4-pyridylimidazole;

5-(4-fluorophenyl)-2-[(4-methylsulfonylphenyl)methylthio]-4-pyridylimidazole;

2-[(4-aminosulfonylphenyl)methylthio]-5-(4-fluorophenyl)-4-pyridylimidazole;

2-[2-(4-aminosulfonylphenyl)ethylthio]-5-(4-fluorophenyl)-4-pyridylimidazole;

5-(4-fluorophenyl)-2-[2-(4-methylthiophenyl)ethylthio]-4-pyridylimidazole;

5-(4-fluorophenyl)-2-[2-(4-methylsulfonylphenyl)ethylthio]-4-pyridylimidazole;

5-(4-fluorophenyl)-2-[(3-methylthiophenyl)methylthio]-4-pyridylimidazole;

5-(4-fluorophenyl)-2-[(2-methylthiophenyl)methylthio]-4-pyridylimidazole;

5-(4-fluorophenyl)-2-[(3-methylsulfinylphenyl)methylthio]-4-pyridylimidazole;

5-(4-fluorophenyl)-2-[(2-methylsulfinylphenyl)methylthio]-4-pyridylimidazole;

5-(4-fluorophenyl)-2-[(4-hydroxy-3-methylthiophenyl)methylthio]-4-pyridylimidazole;

5-(4-fluorophenyl)-2-[(4-hydroxy-3-methylthiophenyl)methylthio]-4-pyridylimidazole;

2-[(5-chloro-2-hydroxy-3-methylthiophenyl)methylthio]-5-(4fluorophenyl)-4-pyridylimidazole;and

2-[(5-chloro-2-hydroxy-3-methylsulfinylphenyl)methylthio]-5-(4-fluorophenyl)-4-pyridylimidazole.

It should be taken into account that in the case of the compoundsaccording to the invention the following structural equilibrium exists:

Even if only the 5-aryl-4-heteroarylimidazole derivatives of the generalformula I are described in the description and in the claims for easierunderstanding, the present invention therefore also comprises the4-aryl-5-heteroarylimidazole derivatives.

The present invention also relates to a process for the preparation of acompound of the general formula I, in which an imidazole-2-thione of thegeneral formula II

in which Ar and Het are as defined above, is reacted with a compound ofthe general formula III

in which A, R¹, R², n and m are as defined above and X is a leavinggroup, to give a compound of the general formula I or a pharmaceuticallytolerable salt thereof.

In this process, the compound according to the invention is prepared ina nucleophilic substitution reaction from corresponding aralkyl,aralkenyl or aralkynyl precursors of the formula II and the5-aryl-4-heteroarylimidazole-2-thiones of the formula II in the presenceor absence of various bases, such as sodium hydride, alkali metalhydroxide, carbonate or acetate.

The precursors of the formula III include a leaving group X, which canbe, for example, chlorides, bromides, iodides, acetates or themethanesulfonic acid, toluenesulfonic acid and trifluoromethanesulfonicacid esters of the corresponding alcohols, or further leaving groupsknown as suitable to the person skilled in the art.

Solvents used are either dipolar aprotic solvents, in particular DMF, orprotic solvents, such as alcohols, in particular ethanol but also asmixtures with ethers, such as THF.

A particularly preferred embodiment of the process is the reaction ofthe aralkyl, aralkenyl or arylkynyl precursors with5-(4-fluorophenyl)-4-(4-pyridyl)-imidazolethione (CAS Reg. No.72882-75-8) in ethanol/THF in the presence of sodium carbonate or sodiumacetate at a temperature of 20-80° C.

For example,5-(4-fluorophenyl)-2-[2-(methylsulfinyl)-benzylthio]-4-(4-pyridinyl)-1H-imidazoleand5-(4-fluorophenyl)-2-[4-(methylsulfinyl)benzylthio]-4-(4-pyridinyl)-1H-imidazolesare obtained by base-catalyzed substitution of the positionally isomeric(methylsulfinyl)benzyl chlorides with5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole-2-thione.

Under the same conditions, 3-(methylsulfinyl)benzyl chloride forms no5-(4-fluorophenyl)-2-[3-(methylsulfinyl)benzylthio]-4-(4-pyridinyl)-1H-imidazole.It is prepared by selective oxidation with H₂O₂ in glacial acetic acidof5-(4-fluorophenyl)-2-[3-(methylthio-benzylthio]-4-(4-pyridinyl)-1H-imidazole,which can be prepared by substitution of 3-(methylthio)benzyl chlorideby 5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole-2-thione.

Differences also exist in the synthesis route for the various precursorsin the case of the methylthio and methylsulfinyl compounds. Thusp-methylsulfinylbenzyl chloride is obtained from p-methylthiobenzylalcohol by chlorination and S-oxidation. The o-methylsulfinylbenzylchloride is accessible via the S-methyl ether of thiosalicylic acid,which is reduced to the benzyl alcohol by LiAlH₄, chlorinated withthionyl chloride and oxidized on the S atom using H₂O₂ in glacial aceticacid. m-Methylthiobenzyl chloride can likewise be prepared bychlorosulfonation, S-reduction, S-methylation, C-reduction andchlorination starting from benzoic acid. The preparation of the otherintermediates of the formula III is carried out by conventional methodsknown to the person skilled in the art.

As a special case,2-hydroxybenzylthio-5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-imidazoles ofthe general formula I (R²=OH) can also be prepared from suitablehydroxymethylphenols and5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-imidazole-2-thione byacid-catalyzed substitution. Corresponding alkylthiohydroxymethylphenolsof the formula III are obtained from phenolcarboxylic acid esters bychlorosulfonation, S-reduction, S-alkylation and final C-reduction. The(alkylthio)benzylthioimidazoles prepared in this way can be oxidizedselectively to the (alkylsulfinyl)benzylthioimidazoles usingH₂O₂/glacial acetic acid.

The imidazole-2-thione of the general formula II also employed as astarting material in the process of the present invention can beprepared by conventional methods known to the person skilled in the art.

For example, the preparation can be carried out according to the routedescribed by I. Lantos et al. (J. Med. Chem. 1984, 27, 72-75). Accordingto this method, cyanohydrin benzoates, which can only be obtained invery small yields from aromatic aldehydes, are condensed with a second,aromatic aldehyde to give unsymmetrical benzoins, and these are finallyring-closed with thiourea to give the imidazole-2-thiones.

According to another method described by Bender et al. in EP 0 231 622A2, the ring closure is carried out using azirenes which add in situwith hydrogen thiocyanate to give the desired imidazo-2-thiones.

The last-mentioned method is presently illustrated in greater detail inexample 1.I.

The compounds of the formula I according to the invention show anantiinflammatory activity in vivo, and in vitro show an inhibition ofthe release of various cytokines, and they are suitable as inhibitors ofthe arachidonic acid cascade. They are thus suitable for the treatmentof diseases in which increased release rates of cytokines or of theeicosanoid mediators are responsible for the origin or the progressivecourse of these diseases.

The present invention thus also comprises medicaments which contain acompound of the general formula I or a pharmaceutically tolerable saltthereof and, if appropriate, customary vehicles and excipients.

Furthermore, the compounds of the general formula I according to theinvention are in particular also suitable for the production ofmedicaments for the treatment of diseases in which the increased releaserate of cytokines,, such as IL-1b and TNF-α, or of the eicosanoidmediators, such as hydroperoxyeicosatetraenoic acids (HPETEs) andhydroxyeicosatetraenoic acids (HETEs), leukotrienes as products of the5-lipoxygenase metabolic pathway and prostaglandins as products of thecyclooxygenase (1/2) metabolic pathway are responsible for the origin orthe progressive course of the diseases. In particular, the compounds ofthe general formula I according to the invention are suitable for theproduction of medicaments having antiinflammatory action.

Preferably, the compounds of the general formula I according to theinvention are used for the production of medicaments for the treatmentof the following diseases:

rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout,multiple sclerosis, toxic shock syndrome, sepsis, adult respiratorydistress syndrome (ARDS), inflammatory bowel disease (IBD), cachexia,AIDS-related complex (ARC), ulcerative colitis, Crohn's disease,inflammatory skin diseases and psoriatic arthritis.

The following examples are intended to illustrate the present inventionin greater detail.

EXAMPLE 1 I) Intermediate Compound5-(4-Fluorophenyl)-4-(4-pyridyl)imidazole-2-thione

a) 2-Cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethen-1-ol hydrochloride

17.3 g (0.75 mol) of metallic sodium were treated dropwise with 250 mlof absolute ethanol. 75.8 g (0.5 mol) of ethyl isonicotinate and 67.6 g(0.5 mol) of 4-fluorophenylacetonitrile were added to the ethoxide. Thereaction mixture was stirred at 100° C. for 15 min. The mixture was thencooled in an ice bath and treated with 600 ml of dist. water. Onacidifying to pH 1 using 90 ml of conc. HCl, the title compounddeposited as a yellow precipitate. The precipitate was filtered off,washed with dist. water and dried over P₂O₅ in vacuo. Yield: 85.0 g(62%).

¹H NMR ([D₆]DMSO/CDCl₃) δ(ppm): 8.8 (AA′, 2H, 4-pyridyl), 7.8 (m, 2H,4-F-phenyl), 7.7 (BB′, 2H, 4-pyridyl), 7.1 (m, 2H, 4-F-phenyl), enolsignal not visible.

b) 2-(4-Fluorophenyl)-1-(4-pyridyl)ethanone

40.6 g (0.15 mol) of 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethen-1-olhydrochloride were refluxed with vigorous stirring for 19 h in 130 ml of48% strength hydrobromic acid. The reaction mixture was cooled in an icebath, and the precipitate deposited (4-fluorophenylacetic acid) wasfiltered off and washed with dist. water. On neutralizing the filtratewith 80 ml of ammonia water, the title compound deposited as adark-green precipitate. The precipitate was filtered off, washed withdist. water and dried over P₂O₅ in vacuo: pale gray-beige powder. Yield:14.2 g (45%).

¹H NMR (CDCl₃) δ (ppm): 8.8 (AA′, 2H, 4-pyridyl), 7.8 (BB′, 2H,4-pyridyl), 7.2 (m, 2H, 4-F-phenyl), 7.0 (m, 2H, 4-F-phenyl), 4.3 (s,1H, —CH₂—).

c) 2-(4-Fluorophenyl)-1-(4-pyridyl)ethanone oxime

21.5 g (0.1 mol) of 2-(4-fluorophenyl)-1-(4-pyridyl)-ethanone wassuspended in 330 ml of 50% aqueous methanol. After addition of 36.1 g(0.44 mol) of sodium acetate and 22.0 g (0.32 mol) of hydroxylaminehydrochloride, the reaction mixture was refluxed for 1 h with stirring.On cooling in an ice bath, the title compound deposited as abeige-colored precipitate. The precipitate was filtered off, washed withdist. water and dried over P₂O₅ in vacuo. Yield: 14.3 g (62%).

¹H NMR (CDCl₃) δ(ppm): 11.7 (s, 1H, oxime OH) , 8.6 (AA′, 2H,4-pyridyl), 7.5 (BB′, 2H, 4-pyridyl), 7.2 (m, 2H, 4-F-phenyl), 6.9 (m,2H, 4-F-phenyl), 4.1 (s, 2H, —CH₂—)

d) 2-(4-Fluorophenyl)-1-(4-pyridyl)ethanone, O-[(4-methylphenyl)sulfonyl]oxime

10.1 g (0.04 mol) of 2-(4-fluorophenyl)-1-(4-pyridyl)ethanone oxime weredissolved in 50 mol of absolute pyridine in an argon atmosphere. Thesolution was cooled to 6° C. and treated dropwise with 10.1 g (0.05 mol)of toluenesulfonyl chloride. After addition was complete, the reactionmixture was stirred at room temperature for 20 h. The mixture was thenpoured onto 500 ml of ice water. The precipitate deposited was filteredoff, washed in the cold with dist. water and dried at 50° C. in a dryingoven. Yield: 14.9 g (88%).

¹H NMR (CDCl₃) δ(ppm): 11.7 (s, 1H, oxime), 8.6 (d, 2H, AA′, 4-pyridyl),7.9 (AA′, 2H, 4-tosyl), 7.5 (BB′, 2H, 4-pyridyl), 7.4 (BB′, 2H,4-tosyl), 6.9-7.1 (m, 4H, 4-F-phenyl), 4.1 (s, 2H, —CH₂—), 2.5 (s, 1H,—CH₃).

e) 5-(4-fluorophenyl) -4-(4-pyridyl) imidazole-2-thione

10.0 g (0.03 mol) of 2-(4-fluorophenyl)-1-(4-pyridyl)-ethanone,O-[(4-methylphenyl) sulfonyl]oxime were dissolved in 56 ml of absoluteethanol in an argon atmosphere. The solution was cooled to 5° C. andtreated dropwise with freshly prepared sodium ethoxide from 0.75 g (0.03mol) of metallic sodium in 30 ml of absolute ethanol. The reactionmixture was stirred at 5° C. for 5 h. After addition of 500 ml ofdiethyl ether, it was stirred for a further 30 min. The precipitatedeposited was filtered off and washed 4× using 50 ml of diethyl ethereach time. The combined ethereal phase was extracted 3× with 90 ml of10% strength hydrochloric acid each time. The aqueous extract wasconcentrated to 40 ml and treated with 5.0 g (0.05 mol) of potassiumthiocyanate. The reaction mixture was refluxed for 1 h with stirring. Onneutralizing with 270 ml of 5% sodium hydrogencarbonate solution thetitle compound deposited as a beige precipitate. The precipitate wasfiltered off, washed with dist. water and dried at 60° C. in a dryingoven. Yield: 5.6 g (79%).

¹H NMR ([D₆]DMSO) δ(ppm): 12.76 (AA′, 2H, 2NH) 8.50 (AA′, 2H,4-pyridyl), 7.50-7.42 (m, 2H, 4-F-phenyl), 7.34-7.25 (m, 4H,4-pyridyl+4-F-phenyl).

¹³C NMR ([D₆]DMSO) δ(ppm): 164.3 162.1 160.0 149.9 135.5 130.8 130.7126.8 124.5 121.8 120.4 116.2 115.7.

IR (KBr) 1/λ [cm⁻¹]: 1602, 1518, 1228, 1161, 1005, 830, 586, 545.

II) Compound according to the invention5-(4-Fluorophenyl)-2-[(4-methylthio)benzylthio]-4-(4-pyridyl)imidazole

5-(4-Fluorophenyl)-4-(4-pyridyl)imidazole-2-thione (343 mg, 1.3 mmol),prepared by the process described above under I), was suspended in 12 mlof a 50% strength solution of ethanol in THF and treated with 123 mg(1.5 mmol) of sodium acetate. 258 mg (1.5 mmol) of (4-methylthio)benzylchloride were introduced into this initial mixture. The reaction mixturewas refluxed for 4 h with stirring. The mixture was filtered and thefiltrate was concentrated. The residue was crystallized using ethylacetate and the crystallizate was filtered off. Yield: 0.35 g (68%).

¹H NMR ([D₆]DMSO): δ(ppm) 8.46-8.43 (AA′, 2H, 4-pyridyl), 7.67-7.05 (m,11H, 4-F-phenyl), 4-CH₃S-phenyl, 4-pyridyl, NH_(Im)), 4.33 (s, 2H,—CH₂—), 2.45 (s, 3H, —SCH₃).

IR (KBr) 1/λ=cm⁻¹: 3429, 1606, 1579, 1504, 1424, 1226, 832.

EXAMPLE 25-(4-Fluorophenyl)-2-[(4-methylsulfinyl)benzylthio]-4-(4-pyridyl)imidazole

5-(4-Fluorophenyl)-4-(4-pyridyl)imidazole-2-thione from example 1.I (546mg, 2.0 mmol) was suspended in an ethanol/THF mixture (1:1, 20 ml) andtreated with sodium acetate (195 mg, 2.4 mmol). After introduction of(4-methylsulfinyl)benzyl chloride (520 mg, 2.8 mmol), the reactionmixture was refluxed for 12 h with stirring. The mixture was filteredand the filtrate was concentrated. The residue was crystallized usingethyl acetate, the crystallizate was filtered off and purified by columnchromatography (cc) (SiO₂/methanol). Yield: 65 mg (8%).

¹H NMR ([D₄]MeOH): δ(ppm) 8.4 (AA′, 2H, 4-pyridyl), 7.6 (AA′, 2H,4-CH₃SO-phenyl), 7.5 (BB′, 2H, 4-CH₃SO-phenyl), 7.4-7.3 (m, 4H,4-pyridyl, 4-F-phenyl), 7.2 (m, 2H, 4-F-phenyl), 7.4-7.1 (m, 11H,4-F-phenyl, 4-CH₃S-phenyl, 4-pyridyl, NH_(Im)), 4.3 (s, 2H, —CH₂—), 2.7(s, 3H, —SOCH₃).

IR (KBr) 1/λ=cm⁻¹: 3426, 1602, 1506, 1226, 1157, 1039, 1007, 835, 582.

EXAMPLE 35-(4-Fluorophenyl)-2-[(4-methylsulfonyl)benzylthio]-4-(4-pyridyl)imidazole

5-(4-Fluorophenyl)-4-(4-pyridyl)imidazole-2-thione from example 1.I (343mg, 1.3 mmol) was suspended in a mixture of ethanol (6 ml) and THF (6ml) and treated with sodium acetate (123 mg, 1.5 mmol).(4-Methylsulfonyl)benzyl chloride (306 mg, 1.5 mmol) were introducedinto this initial mixture. The reaction mixture was refluxed for 5 hwith stirring. The mixture was filtered and the filtrate wasconcentrated. The residue was crystallized using ethyl acetate and thecrystallizate was filtered off. Yield: 0.25 g (45%).

¹H NMR ([D₆]DMSO): δ(ppm) 8.4 (AA′, 2H, 4-pyridyl), 7.9 (AA′, 2H,4-CH₃SO₂-phenyl), 7.6 (BB′, 2H, 4-CH₃SO₂-phenyl), 7.4-7.3 (m, 4H,4-pyridyl, 4-F-phenyl), 7.1 (m, 2H, 4-F-phenyl), 7.4-7.1 (m, 11H,4-F-phenyl, 4-CH₃S-phenyl, 4-pyridyl, NH_(Im)) , 4.4 (s, 2H, —CH₂—) ,3.0 (s, 3H, —SCH₃).

IR (KBr) 1/λ=cm⁻¹: 3426, 1602, 1575, 1506, 1304, 1147, 833, 768, 525.

EXAMPLE 42-[2-(4-Aminosulfonylphenyl)ethylthio]-5-(4-fluorophenyl)-4-(4-pyridyl)imidazole

5-(4-Fluorophenyl)-4-(4-pyridyl)imidazole-2-thione from Example 1.I (343mg, 1.26 mmol) was suspended in ethanol/THF (1:1, 12 ml) and treatedwith sodium acetate (123 mg, 1.5 mmol). 2-(4-Aminosulfonylphenyl)ethylchloride (282 mg, 1.3 mmol) was introduced into this initial mixture.The reaction mixture was refluxed for 5 h with stirring. The mixture wasfiltered and the filtrate was concentrated. The residue was crystallizedusing diisopropyl ether, and the crystallizate was filtered off andrecrystallized from isopropanol. Yield: 0.32 g (60%).

¹H NMR ([D₆]DMSO): δ(ppm) 8.35-8.32 (d, 2H, arom.); 7.82-7.77 (d, 2H,arom.); 7.52-7.06 (m, 6H, arom.); 7.15-7.06 (t, 2H, arom.); 3.36 (t, 2H,J=7.4 Hz, CH₂); 3.08 (t, 2H, CH₂)

IR (KBr) 1/λ=cm⁻¹: 3347, 3251, 1603, 1505, 1335, 1222, 1158, 831, 586,540.

EXAMPLE 52-[(4-Aminosulfonylphenyl)methylthio]-5-(4-fluorophenyl)-4-(4-pyridyl)imidazole

5-(4-Fluorophenyl)-4-(4-pyridyl)imidazole-2-thione from Example 1.I (1.8g, 7.2 mmol) and (4-aminosulfonyl)benzyl bromide (1.63 g, 6.0 mmol) weresuspended in ethanol (120 ml) and treated with sodium carbonate (1.14 g,10.8 mmol). The reaction mixture was refluxed for 4 h with stirring. Themixture was filtered cold and the filtrate was concentrated. The residuewas crystallized using ethyl acetate, and the crystallizate was filteredoff and recrystallized from THF. Yield: 1.1 g (35%).

¹H NMR ([D₆]DMSO): δ(ppm) 8.43-8.40 (d, 2H, arom.); 7.81-7.15 (m,arom.); 4.44 (s, 2H, CH₂);

IR (KBr) 1/λ=cm⁻¹: 3431, 3045, 2926, 1604, 1508, 1304, 1145, 835, 528.

EXAMPLE 62-[2-(4-Methylthiophenyl)ethylthio]-5-(4-fluorophenyl)4-(4-pyridyl)imidazole

5-(4-Fluorophenyl)-4-(4-pyridyl)imidazole-2-thione from Example 1.I (406mg, 1.5 mmol) and (2-[(4-methylthio)phenyl]ethyl chloride (350 mg, 1.87mmol) were suspended in ethanol (30 ml) and treated with sodiumcarbonate (280 g, 2.7 mmol). The reaction mixture was refluxed for 48 hwith stirring. The mixture was filtered cold and the filtrate wasconcentrated. The residue was crystallized using ethyl acetate, and thecrystallizate was filtered off. Crude yield: 0.3 g (55%).Recrystallization from isopropanol yields 0.1 g of colorless substance(18%).

¹H NMR ([D₆]DMSO): δ(ppm) 8.42-8.39 (d, 2H, arom.); 7.52-7.12 (m, 10H,arom.); 3.39-3.32 (t, 2H, CH₂); 3.02-2.98 (t, 2H, CH₂); 2.43 (s, 3H,CH₃)

IR (KBr) 1/λ=cm⁻¹: 3424, 3044, 2924, 1603, 1517, 1226, 1002, 842, 831.

EXAMPLE 75-(4-Fluorophenyl)-2-[2-(4-methylsulfonylphenyl)ethylthio]-4-(4-pyridyl)imidazole

5-(4-Fluorophenyl)-4-(4-pyridyl)imidazole-2-thione from Example 1.I(1.63 g, 6 mmol) and 2-[(4-methylsulfonyl)phenyl]ethyl chloride (1.6 g,7.3 mmol) were suspended in ethanol (120 ml) and treated with sodiumcarbonate (1.14 g, 10.8 mmol). The reaction mixture was refluxed for 60h with stirring. The mixture was filtered cold and the filter residuewas suspended in water. The water-insoluble constituents were filteredoff with suction, dried and recrystallized from MeOH: yield 0.9 g.

The ethanol filtrate of the reaction solution was concentrated. Theresidue of this phase was crystallized using MeOH and the crystallizatewas filtered off. Yield: 0.6 g Total yield: 1.5 g (55%)

¹H NMR ([D₆]DMSO): δ(ppm) 8.42 (s, 2H, arom.); 7.88-7.83 (m, 2H, arom.);7.56-7.41 (m, 6H, arom.); 7.21-7.17 (t, 2H, arom.); 3.44-3.41 (t, 2H,CH₂); 3.2-3.1 (m, 5h, CH₂, CH₃)

IR (KBr) 1/λ=cm⁻¹: 3435, 3044, 2934, 1605, 1509, 1411, 1302, 1232, 1144,1087, 1007, 833.

EXAMPLE 85-(4-Fluorophenyl)-2-[(3-methylthiophenyl)methylthio]-4-(4-pyridyl)-1H-imidazole

a) 3-Chlorosulfonylbenzoic acid

Benzoic acid (30.5 g, 0.25 mol) is treated with chlorosulfonic acid (10ml/1.05 mol). The reaction mixture is heated to 120° C. in the course of20 min with stirring. To complete the reaction, it is stirred for 45 minat 125° C. until the absence of the evolution of gas. The reactionmixture is cooled to room temperature (RT) and added to 300 ml of icewith stirring. The cream-colored precipitate is filtered off, thoroughlywashed with ice water and dried. Yield: 40.8 g (74%)

¹H NMR ([D₆]DMSO) δ(ppm): 8.49 (6 variable, s, 1H, carboxyl OH);8.28-8.24 (m, 1H, C2-H); 7.98-7.88 (m, 2H, C4-H, C6-H); 7.58-7.51 (m,1H, C5-H)

b) Dithio-di-m-benzoic acid

90 ml of conc. hydrochloric acid are added to a solution of3-chlorosulfonylbenzoic acid (20 g, 0.091 mol) in 135 ml of ethanol.Zinc dust (32 g, 0.49 mol) is introduced in portions in the course of 2h into this initial mixture with stirring and initial ice-cooling. After30 min, the cooling is removed and the reaction mixture is stirredfurther at RT. After addition is complete, the reaction mixture isstirred at RT for a further 3 h. The reaction mixture is filtered andthe residue is washed with a little ethanol. The combined filtrates aretreated in portions with solid FeCl₃ with stirring until the solutionassumes a permanent brown coloration. On allowing to stand at RT, thetitle compound deposits within a few minutes as a beige precipitate. Thecrude product is filtered off, washed with H₂O and dried. Yield: 7.5 g(54%)

¹H NMR ([D₆]DMSO): δ(ppm) 8.10-8.03 (m, 2H, C2-H+C2′-H); 7.90-7.74 (m,4H, C4-H, C6-H, C4′-H, C6′-H); 7.60-7.50 (m, 2H, C5-H. C5′-H); carboxylOH not visible

c) 3-Methylthiobenzoic acid

Na₂S×6-9 H₂O (3.1 g, 14 mmol) is introduced into a solution ofdithio-di-m-benzoic acid (7.5 g, 25 mmol) in 125 ml of 1N sodiumhydroxide solution. The reaction mixture is heated to reflux temperaturein the course of 15 min with stirring and stirred under reflux for afurther 60 min. The pale brown suspension is cooled to RT and treated inportions with dimethyl sulfate (5.4 ml/56 mmol) at 30° C. The reactionmixture is stirred at RT for 2.5 h and under reflux for a further 30min. The reaction mixture is cooled to RT, made up with 30 ml of dist.H₂O and acidified dropwise to pH=1 using conc. hydrochloric acid. Thepale-brown precipitate is filtered off, washed with H₂O and dried. Thecrude product is recrystallized from 300 ml of 50% strength aqueousmethanol with addition of active carbon (0.5 g) and filtered hot:silver-white flakes, yield; 3.7 g (44%)

¹H NMR ([D₆]DMSO): δ(ppm)=7.78-7.70 (m, 2H, C2-H, C4-H); 7.54-7.41 (m,2H, C5-H, C6-H); 2.53 (s, 3H, methyl); carboxyl OH not visible

¹³C NMR ([D₆]DMSO): δ(ppm)=166.84; 138.89; 131.43; 129.98; 129.08;125.97; 125.58; 14.46

d) 3-Hydroxymethyl-1-methylthiobenzene 95% LiAlH₄ (1.6 g, 40 mmol) isintroduced in 75 ml of absolute THF into a 3-necked flask which isheated and flushed with argon. A solution of 3-methylthiobenzoic acid(5.2 g, 31 mmol) in absolute THF (25 ml) is added dropwise to thisinitial mixture with ice-cooling in the course of 15 min such that onlya moderate evolution of gas takes place. After addition is complete, thecooling is removed and the reaction mixture is stirred at RT for 30 minand 60-65° C. for a further 2 h. The reaction mixture is cooled to RTand treated cautiously with ice water with ice-cooling. The precipitateof Al(OH)₃ is dissolved by addition of 10% strength sulfuric acid. Theorganic phase is separated off and the aqueous-acidic phase is extracted3× with diethyl ether. The combined ethereal extracts are washed 2× withsaturated NaCl solution and 2× with dist. H₂O, dried over Na₂SO₄ andconcentrated. The oily crude product is purified by distillation in abulb tube (2.5×10⁻² mbar, 155-175° C.): colorless oil, yield: 4.5 g(94%).

¹H NMR (CDCl₃): δ(ppm)=7.32-7.10 (m, 4H, Ph—H); 4.67 (s, 2H, methylene);2.49 (s, 3H, methyl); 1.72 (s, 1H, exchangeable, OH)

e) 3-Chloromethyl-1-methylthiobenzene

3-Hydroxymethyl-1-methylthiobenzene (3.3 g, 21 mmol) is dissolved inabsolute CH₂Cl₂ (20 ml) under an argon atmosphere. A solution of SOC1₂(2.6 g, 21 mmol) in absolute CH₂Cl₂ (10 ml) is added dropwise withstirring to this initial mixture in the course of 15 min, initiallyunder reflux, then at an internal temperature of 30° C. The reactionmixture is stirred under reflux for 2.25 h. The reaction mixture isconcentrated and the oily crude product is purified by bulb tubedistillation (7.9×10⁻² mbar, 125-140° C.): colorless oil; yield: 3.3 g(88%)

¹H NMR (CDCl₃): δ(ppm)=7.28-7.16 (m, 4H, Ph—H); 4.55 (s, 2H, methylene);2.49 (s, 3H, methyl)

f)5-(4-Fluorophenyl)-2-[(3-methylthiophenyl)methylthio]-4-(4-pyridyl)-1H-imidazole3-Chloromethyl-1-methylthiobenzene (690 mg, 4.1 mmol) is dissolved in 60ml of absolute ethanol in an argon atmosphere.5-(4-Fluorophenyl)-4-(4-pyridyl)imidazole-2-thione (1.1 g, 4.1 mmol) isintroduced into this initial mixture. The reaction mixture is stirredunder reflux for 11 h. The heating is removed and the orange-coloredsolution is subsequently stirred at RT for 61 h. The yellow precipitateis filtered off and dried. Yield: 1.21 g (73%)

¹H NMR ([D₆]DMSO): δ(ppm)=8.67 (m, 2H, AA′ 4-Pyr); 7.91 (m, 2H,BB′4-Pyr); 7.63-7.56 (m, 2H, 4-F—Ph); 7.43-7.16 (m, 6H,4-F—Ph+3-H₃CS—Ph); 4.46 (s, 2H, methylene); 2.40 (s, 3H, methyl); NH notvisible

¹³C NMR ([D₆]DMSO): δ(ppm)=165.05; 160.14; 148.91; 143.33; 141.29;138.69; 138.15; 136.88; 131.30; 131.13; 130.58; 128.96; 126.21; 125.42;124.71; 121.44; 116.46; 116.03; 35.95; 14.52

EXAMPLE 95-(4-Fluorophenyl)-2-[(3-methylsulfinylphenyl)methylthio]-4-(4-pyridyl)-1H-imidazole

5-(4-Fluorophenyl)-2-[(3′-methylthiophenyl)methylthio]-4-(4-pyridyl)-1H-imidazole(example 8, 500 mg, 1.2 mmol) is suspended in 7 ml of glacial aceticacid. 35% strength H₂O₂ solution (0.13 ml/1.3 mmol) is added dropwise tothe initial mixture. The reaction mixture is stirred at RT for 20.5 h.The reaction mixture is diluted with 5 ml of H₂O and adjusted dropwiseto pH=9 using conc. ammonia water with ice-cooling. The aqueoussupernatant is decanted off and extracted 3× with ethyl acetate. Theoily residue is taken up in ethyl acetate. The organic solutions arecombined, washed 3× with saturated NaCl solution, dried over Na₂SO₄ andconcentrated. The oily crude product is purified (RP-18/MeOH) by cc:pale yellow powder, yield: 156 mg (31%).

IR (KBr): 1/λ[cm⁻]=3099, 3057, 2937, 1601, 1500, 1418, 1228, 1019, 837,829, 694;

¹H NMR ([D₃]MeOD): δ(ppm)=8.41 (dd, 2H, J=5.0 Hz, J=1.4 Hz, AA′4-Pyr);7.58-7.37 (m, 8H, BB′4-Pyr, 4-F—Ph, 3-H₃CSO—Ph); 7.21-7.13 (m, 2H,4-F—Ph); 4.37 (s, 2H, methylene); 2.67 (s, 3H, methyl);

¹³C NMR ([D₃]MeOD): δ(ppm)=167.0; 162.0; 150.2; 149.8; 146.6; 141.4;133.2; 132.0; 131.9; 130.9; 125.1; 123.9; 123.0; 117.3; 116.9; 43.7;39.6.

EXAMPLE 105-(4-Fluorophenyl)-2-[(2-methylsulfinylphenyl)methylthio]-4-(4-pyridyl)-1H-imidazole

a) 2-Methylthiobenzoic acid

Thiosalicylic acid (0.5 g, 3.2 mmol) is dissolved in 3.2 ml of 10%strength sodium hydroxide solution under an argon atmosphere. Dimethylsulfate (0.31 ml/3.2 mmol) is added dropwise with stirring to thisinitial mixture at RT. The reaction mixture is stirred at RT for 15 minand under reflux for a further 60 min. The reaction mixture is cooled toRT and acidified to pH=1 using 10% strength hydrochloric acid withwater-cooling. The white precipitate is filtered off, washed with H₂Oand dried. Yield: 520 mg (96%).

¹H NMR ([D₆]DMSO): δ(ppm)=7.91 (dd, 1H, J=7.8 Hz, J=1.3 Hz, C3-H); 7.56(ddd, 1H, J=7.7 Hz, J=7.6 Hz, J=1.5 Hz; C5-H); 7.38-1.34 (m, 1H, C6-H);7.22 (m, 1H, C4-H); 2.40 (s, 3H, methyl); carboxyl-OH not visible

b) 2-Hydroxymethyl-1-methylthiobenzene

95% LiAlH₄ (1.6 g, 40 mmol) is introduced in 75 ml of absolute THF intoa 3-necked flask which is heated and flushed with argon. A solution of2-methylthiobenzoic acid (5.2 g, 31 mmol) in 25 ml of absolute THF isadded dropwise with ice-cooling to this initial mixture in the course of15 min such that only moderate evolution of gas takes place. Afteraddition is complete, the cooling is removed and the reaction mixture isstirred at RT for 30 min and at 60-65° C. for a further 2 h. Thereaction mixture is cooled to RT and treated carefully with ice-water.The precipitate of Al(OH)₃ is dissolved by addition of 10% strengthsulfuric acid. The organic phase is separated off and the aqueous-acidicphase is extracted 3× with diethyl ether. The combined ethereal extractsare washed 2× with saturated NaCl solution and 2× with dist. H₂O, driedover Na₂SO₄ and concentrated. The oily crude product is purified bydistillation in a bulb tube (2.5×10⁻² mbar, 155-175° C.): colorless oil,yield: 4.5 g (94%).

¹H NMR (CDCl₃): δ(ppm)=7.39-7.36 (m, 1H, C6-H); 7.31-7.14 (m, 3H, C3-H,C4-H, C5-H); 4.76 (s, 2H, methylene); 2.49 (s, 3H, methyl); 2.03 (s, 1H,OH)

c) 2-Chloromethyl-1-methylthiobenzene

2-Hydroxymethyl-1-methylthiobenzene (3.3 g, 21 mmol) is dissolved in 20ml of absolute CH₂Cl₂ under an argon atmosphere. A solution of SOCl₂(2.6 g, 21 mmol) in 10 ml of absolute CH₂Cl₂ is added dropwise withstirring to this initial mixture in the course of 15 min, first underreflux, then at an internal temperature of 30° C. The reaction mixtureis stirred under reflux for 2.25 h. The reaction mixture is concentratedand the oily crude product is purified by bulb tube distillation(7.9×10⁻² mbar, 125-140° C.): colorless oil; yield: 3.3 g (88%).

¹H NMR (CDCl₃): δ(ppm)=7.40-7.13 (m, 4H, Ph-H); 4.74 (s, 2H, methylene);2.51 (s, 3H, methyl)

d) 2-Chloromethyl-1-methylsulfinylbenzene2-Chloromethyl-1-methylthiobenzene (3.0 g, 17.4 mmol) is dissolved in 35ml of glacial acetic acid. A solution of 35% strength H₂O₂ solution(2.15 g, 22 mmol) in 10 ml of glacial acetic acid is added dropwise inthe course of 5 min to this initial mixture with ice-cooling to 3-8° C.The cooling is removed and the reaction mixture is stirred at RT for 8h, further 35% strength H₂O₂ solution (0.15 g, 1.5 mmol or 0.1 g, 1.0mmol) being added after 6 h and 7 h respectively. The reaction mixtureis treated with ice and adjusted to pH=4 using conc. ammonia water. Thewhite precipitate is filtered off, washed with H₂O and dried. Theaqueous-acidic solution is adjusted to pH=7 using conc. ammonia water.The precipitate is filtered off, washed with H₂O and dried. Theaqueous-acidic solution is extracted with ethyl acetate. The organicextract is washed 2× with 8% strength NaHCO₃ solution and 2× withsaturated NaCl solution, dried over Na₂SO₄ and concentrated: yellow oilwhich slowly crystallizes at RT. Total yield: 3.12 g (95%).

¹H NMR (CDCl₃): δ(ppm)=8.07 (dd, 1H, J=7.8 Hz, 1.4 Hz, C6-H); 7.62 (ddd,1H, J=7.4 Hz, J=7.2 Hz, J=1.6 Hz, C4-H); 7.52 (ddd, 1H, J=7.5 Hz, J=7.3Hz. J=1.6 Hz, C5-H); 7.43 (dd, 1H, J=7.5 Hz, J=1.6 Hz, C3-H); 4.83 (d,1H, J=11.7 Hz, methylene); 4.65 (d, 1H, J=11.7 Hz, methylene); 2.85 (s,3H, methyl);

¹³C NMR (CDCl₃): δ(ppm)=145.33; 134.34; 131.56; 130.61; 130.52; 124.25;44.06; 41.64

f)5-(4-Fluorophenyl)-2-[(2-methylsulfinylphenyl)-methylthio]-4-(4-pyridyl)-1H-imidazole

5-(4-Fluorophenyl)-4-(4-pyridyl)-1H-imidazole-2-thione (0.28 g, 1.03mmol) and 2-chloromethyl-1-methylsulfinylbenzene (0.18 g, 0.95 mmol) aresuspended in EtOH (15 ml) under protective gas (argon) and the mixtureis heated under reflux (internal temperature (IT) 77° C.) for 4 h. Themixture turns deep orange-red and clears. The mixture is thenconcentrated and the orange-red-colored residue is dried (0.48 g). Theproduct is dissolved in a little warm MeOH and treated dropwise withethyl acetate until deposition begins. Crystallization takes placeslowly in the cold. Yield: 230 mg (54%).

IR (KBr): 1/λ[cm⁻¹]=3057, 2979, 2919, 2901, 2625, 1634, 1606, 1556,1522, 1490, 1470, 1350, 1223, 1213, 1155, 1062, 1033, 969, 843, 812, 740

¹H NMR ([D₃]MeOD); δ(ppm)=8.57 (m, 2H, AA′. 4-Pyr); 8.01 (m, 2H, BB′4-Pyr); 7.95 (d, 1H, J=7.2 Hz, C3′-H); 7.62-7.47 (m, 5H, 4-F—Ph, C4′-H,C5′-H, C6′-H); 7.33-7.24 (m, 2H, 4-F—Ph); 4.62 (d, 1H, 2J=13.6 Hz,methylene); 4.50 (d, 1H, 2J=13.6 Hz, methylene); 2.87 (s, 3H, methyl)

¹³C NMR ([D₃]MeOD): δ(ppm)=167.6; 162.7; 152.3; 145.3; 143.8; 142.3;138.9; 136.7; 133.4; 132.8; 132.5; 132.4; 132.0; 130.7; 126.9; 125.0;123.5; 117.9; 117.5; 43.5; 35.1

EXAMPLE 115-(4-Fluorophenyl)-2-[(4-hydroxy-3-methylthiophenyl)-methylthio]-4-(4-pyridyl)-1H-imidazole

a) Ethyl 4-methoxybenzoate

Ethyl 4-hydroxybenzoate (15.0 g, 0.09 mol) is stirred into an initialmixture of KOH (6.3 g, 0.11 mol) in dist. water (60 ml) under protectivegas. Dimethyl sulfate (8.8 ml, 0.09 mol) is added dropwise to the clearsolution with stirring and ice-cooling such that the temperature doesnot exceed 15° C. After addition is complete, the cooling is removed,and to complete the reaction the reaction mixture is stirred at RT for45 min and under reflux for 2 h, then cooled to RT. The deposited oil istaken up in diethyl ether (50 ml). The aqueous phase separated off isextracted with diethyl ether (150 ml), and the ethereal extractsobtained are combined, washed with sodium hydroxide solution (10%strength, 50 ml) and with saturated NaCl solution, dried over Na₂SO₄sicc. and concentrated in vacuo: colorless oil, yield: 15.7 g (97%).

¹H NMR ([D₆]DMSO): δ(ppm): 8.00 (2H, J=6.9 Hz, J=2.2 Hz, AA′4-methyl-O—Ph); 6.92 (dd, 2H, J=6.9 Hz, J=1.8 Hz, BB′ 4-H₃C—O—Ph); 4.35(q, 2H, J=7.1 Hz, methylene); 3.86 (s, 3H, O-methyl); 1.38 (t, 3H, J=7.1Hz, methyl).

b) Ethyl 3-chlorosulfonyl-4-methoxybenzoate

A solution of ethyl 4-methoxybenzoate (10.25 g, 57 mmol) in CCl₄ (40 ml)is cooled to −15° C. and treated dropwise with chlorosulfonic acid (10.4ml, 156 mmol) in the course of 15 min, the temperature rising to −10° C.After addition is complete, the reaction mixture is warmed to RT withstirring in the course of 30 min and then stirred at 40-50° C. for 1.5h. The heating is removed and the reaction mixture is stirred at RT in agentle stream of argon for 64 h to complete the chlorination. Thereaction mixture is added to a suspension of ice (25 g) in CCl₄ (50 ml)with ice-cooling and vigorous stirring. It is stirred vigorously for 3min. The organic phase is separated off and the aqueous phase isextracted 3 times with further CH₂Cl₂ (150 ml). The combined organicextracts are washed with saturated NaCl solution, dried over Na₂SO₄sicc. and concentrated: a crystalline, white residue of a mixture ofester and free acid in the ratio 1:1 remains, which is dried on an oilpump, yield 6.7 g (42%)

¹H NMR ([D₆]DMSO); δ(ppm): 8.63 (d, 1H, J=2.1 Hz, C2-H); 8.37 (dd, 1H,J=8.8 Hz, J=2.1 Hz, C6-H); 7.19 (d, 1H, J=8.8 Hz, C5-H); 4.41 (q, 2H,J=7.1 Hz, methylene); 4.14 (s, 3H, O-methyl); 1.41 (t, 3H, J=7.2 Hz,methyl).

c) 4-Methoxy-3-methylthiobenzoic acid

In the course of 10 min, Ph₃P (20.5 g, 78 mmol) in a suspension of themixture of 3-chlorosulfonyl-4-methoxybenzoic acid and ethyl3-chlorosulfonyl-4-methoxybenzoate (5.1 g, 19.3 mmol, based on the massaverage of ester and acid), obtained under b) is introduced in portionsinto 50 ml of toluene. After addition is complete, the reaction mixtureis stirred at RT for 4.5 h. The fine-crystalline precipitate (Ph₃Poxide) is filtered off and washed with toluene. The combined filtratesare extracted 4 times with 30 ml of 10% strength sodium hydroxidesolution (120 ml) each time. The aqueous-alkaline extracts are combined,treated with dimethyl sulfate (2 ml/21 mmol), stirred at RT for 2 h andfinally heated to boiling temperature. The reaction mixture is cooled toRT and acidified to pH 1 using 20% strength hydrochloric acid withice-cooling. The white precipitate is filtered off, washed with dist.water and dried. Yield 2.8 g (74%)

¹H NMR ([D₃]MeOD): δ(ppm)=7.86-7.79 (m, 2H, C2-H+C6-H); 6.98 (d, 1H,J=8.4 Hz, C5-H); 3.93 (s, 3H, O-methyl); 2.43 (s, 3H, S-methyl)

d) 4-Hydroxy-3-methylthiobenzoic acid

4-Methoxy-3-methylthiobenzoic acid (0.5 g, 2.5 mmol) is suspended in 7ml of a mixture of glacial acetic acid and 48% strength HBr (1+1). Thereaction mixture is stirred under reflux for 6 h. The reaction mixtureis cooled to RT and added to 20 ml of H₂O. The aqueous solution isadjusted to pH=2 using 10% strength Na₂CO₃ solution and extracted 4×using 20 ml of diethyl ether each time. The organic extracts arecombined, washed 2× with saturated NaCl solution, dried over Na₂SO₄ andconcentrated: dirty-brown oil, which crystallizes on allowing to standat RT. The crystallizate is dried, washed with H₂O with stirring,filtered off and dried. Yield: 240 mg (52%).

¹H NMR (CDCl₃): δ(ppm)=8.29 (d, 1H, J=2.2 Hz, C2-H); 8.02 (dd, 1H, J=8.5Hz, J=2.2 Hz. C6-H); 7.05 (d, 1H, J=8.5 Hz, C5-H); 2.38 (s, 3H, methyl);carboxyl OH and phenol OH not visible

¹³C NMR ([D₆]DMSO): δ(ppm)=167.28; 158.10; 128.01; 127.03; 125.47;122.37; 114.00

e) 4-Hydroxymethyl-2-methylthiophenol

95% LiAlH₄ (0.55 g, 14 mmol) is introduced in absolute THF (10 ml) intoa three-necked flask which is heated and flushed with argon. A solutionof 4-hydroxy-3-methylthiobenzoic acid (1.37 g; 7.4 mmol) in absolute THF(15 ml) is added dropwise to this initial mixture with ice-cooling inthe course of 5 min such that only moderate evolution of gas takesplace. After addition is complete, the cooling is removed and thereaction mixture is stirred at RT for 30 min and at 55-65° C. for afurther 21 h. After the reaction mixture has cooled to RT, it is treatedcarefully with ice water with ice-cooling. The basic Al(OH)₃ precipitateis dissolved by addition of 10% strength sulfuric acid and the aqueous,acidic solution (pH=1) is extracted with diethyl ether (150 ml). Thephenolic product is extracted from the combined ethereal extract using 2portions of sodium hydroxide solution (10%, 50 ml). The alkaline sodiumhydroxide extract is adjusted to pH=7 using hydrochloric acid (20%strength), the precipitate is taken up using diethyl ether (50 ml), andthe neutral aqueous solution is extracted with diethyl ether (100 ml).The combined, ethereal extract is washed with saturated NaCl solution,dried over Na₂SO₄ and concentrated: a crystalline, white residueremains.

Yield: 670 mg (57%).

¹H NMR (CDCl₃): δ ppm=7.50 (d, 1H, J=2.0 Hz, C3-H);

7.24 (dd, 1H, J=8.4 Hz, J=2.0 Hz, C5-H); 6.97 (d, 1H, J=8.3 Hz, C6-H);4.60 (s, 2H, methylene); 2.34 (s, 3H, methyl); hydroxyl OH and phenol OHnot visible

f)5-(4-Fluorophenyl)-2-[(4′-hydroxy-3′-methylthiophenyl)methylthio]-4-(4-pyridyl)-1H-imidazole

5-(4-Fluorophenyl)-4-(4-pyridyl)-1H-imidazol-2-thione (200 mg, 0.7 mmol)is suspended in glacial acetic acid (5 ml) and dissolved by addition ofconc. hydrochloric acid (10 drops). 4-Hydroxymethyl-2-methylthiophenol(140 mg, 0.8 mmol) is introduced into the deep orange-colored solution.The reaction mixture is stirred at RT for 2 h. The reaction mixture isdiluted with dist. H₂O (5 ml) and the aqueous solution is adjusteddropwise to pH=8 using conc. ammonia water. The orange-coloredprecipitate is washed by stirring in situ at RT for 45 min, filteredoff, thoroughly washed with H₂O and dried, then digested with a littlemethanol. The methanolic supernatant is filtered off, and the residue isagain washed with methanol and dried: slightly yellowish powder, yield140 mg (47%)

IR (KBr): 1/λ[cm⁻¹]=3423, 3099, 3057, 1600, 1500, 1417, 1227, 1159,1019, 837, 829, 817, 799, 694, 577;

¹H NMR ([D₃]MeOD): δ(ppm)=8.41 (2H, J=4.8 Hz, J=1.4 Hz, AA′ 4-Pyr);7.5-7.3 (m, 4H, BB′ 4-Pyr+4-F—Ph); 7.21-7.12 (m, 2H, 4-F—Ph); 7.0-6.9(m, 2H, C2′-H+C6′-H in 4′-OH—Ph); 6.69 (d, 1H, J=8.0 Hz, C5′-H in4′-OH—Ph); 4.17 (s, 2H, methylene); 2.21 (s, 3H, methyl)

EXAMPLE 125-(4-Fluorophenyl)-2-[(4-hydroxy-3-methylsulfinylphenyl)methylthio]-4-(4-pyridyl)-1H-imidazole

5-(4-Fluorophenyl)-4-(4-pyridyl)-1H-imidazole-2-thione (200 mg, 0.7mmol) is suspended in 5 ml of glacial acetic acid and dissolved byaddition of 15 drops of conc. hydrochloric acid.4-Hydroxymethyl-2-methylthiophenol (140 mg, 0.8 mmol) is introduced inportions into the orange-colored solution. The reaction mixture isstirred at RT for 2.5 h. 35% strength H₂O₂ solution (0.1 ml, 1 mmol) isadded dropwise to the reaction mixture at RT. The reaction mixture isstirred at RT for a further 4 h. The reaction mixture is diluted with 5ml of dist. H₂O and the aqueous solution is adjusted dropwise to pH=8using conc. ammonia water. The precipitate is washed by stirring in situat RT for 15 min, filtered off, washed thoroughly with H₂O and dried.The crude product is washed by stirring with acetone, filtered off anddried: pale orange powder, yield 170 mg (55%)

IR (KBr): 1/λ[cm⁻¹]3435, 3117, 3063, 2360, 2325, 1604, 1503, 1425, 1296,1280, 1230, 1160, 1062, 1013, 999, 833, 818

¹H NMR ([D₃]MeOD): δ(ppm)=8.40 (dd, 2H, J=4.8 Hz, J=1.5 Hz, AA′ 4-Pyr);7.46-7.39 (m, 5H, BB′ 4-Pyr, 4-F—Ph, C2′-H); 7.28 (dd, 1H, J=8.3 Hz,J=2.2 Hz, C6′-H); 7.21-7.12 (m, 2H, 4-F—Ph); 6.78 (d, 1H, J=8.3 Hz.C5′-H); 4.28 (s, 2H, methylene); 2.70 (s, 3H, methyl)

EXAMPLE 132-[(5-Chloro-2-hydroxy-3-methylthiophenyl)methylthio]-5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole

Analogously to example 11 from 5-chloro-2-hydroxy-3-methylthiobenzylalcohol and 5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole-2-thione inglacial acetic acid/conc. hydrochloric acid:

¹H NMR ([D₆]DMSO): δ(ppm)=12.74 (bs, 1H, NH); 8.49 (m, 2H, AA′ 4-Pyr);7.51-7.23 (m, 6H, BB′ 4-Pyr, 4-F—Ph); 7.17 (d, 1H, J=2.3 Hz, C4′-H);6.97 (d, 1H, J=2.3 Hz, C2′-H); 4.38 (s, 2H, methylene); 2.34 (s, 3H,methyl); phenol OH not visible;

IR (KBr): 1/λ[cm⁻¹]=3057, 2919, 2643, 2517, 1604, 1511, 1419, 1259,1225, 1007, 988, 834, 589

EXAMPLE 142-[(2-Hydroxy-5-methylthiophenyl)methylthio]-5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole

Analogously to example 11 from 2-hydroxy-5-methyl thiobenzyl alcohol and5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole-2-thione in glacial aceticacid/conc. hydrochloric acid:

¹H NMR ([D₇]DMF): δ(ppm)=10.7-10.3 (bs, 1H, exchangeable , NH); 8.54 (m,2H, AA′ 4-Pyr); 7.65-7.58 (m, 2H, 4-F—Ph); 7.52 (m, 2H, BB′ 4-Pyr);7.35-7.27 (m, 3H, 4-F—Ph+C2′-H); 7.13 (dd, 1H, J=8.3 Hz, J=2.3 Hz,C4′-H); 6.90 (d, 1H, J=8.4 Hz, C5′-H); 4.46 (s, 2H, methylene); 2.36 (s,3H, methyl); phenol OH not visible;

¹³C NMR ([D₇]DMF): δ(ppm)=165.6; 162.9; 160.7; 155.0; 150.7; 143.5;131.6; 131.4; 131.2; 129.8; 127.6; 126.5; 121.6; 120.0; 117.5; 116.6;116.2; 32.5; 17.5;

IR (KBr): 1/λ[cm⁻¹]=3057, 2913, 2661, 2607, 1602, 1511, 1486, 1418,1382, 1275, 1255, 1230, 1158, 1005, 990, 838, 817, 590, 529

EXAMPLE 152-[(5-Chloro-2-hydroxy-3-methylsulfinylphenyl)methylthio]-5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole

Analogously to example 12 from 5-chloro-2-hydroxy-3-methylthiobenzylalcohol and 5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole-2-thione inglacial acetic acid/conc. hydrochloric acid/H₂O₂:

¹H NMR ([D₃]MeOD): δ(ppm)=8.45 (m, 2H, AA′, 4-Pyr); 7.49-7.42 (m, 6H,BB′ 4-Pyr, 4-F—Ph, C4′-H); 7.39 (d, 1H, J=2.6 Hz, C2′-H); 7.23-7.14 (m,2H, 4-F—Ph); 4.39 (s, 2H, methylene); 2.72 (s, 3H, methyl)

IR (KBr): 1/λ[cm⁻¹]=3420, 3057, 2997, 2925, 2823, 2655, 2517, 2457,2360, 1605, 1509, 1416, 1392, 1265, 1236, 1158, 1086, 1051, 1005, 832,595, 534

EXAMPLE 162-[(2-Hydroxy-5-methylsulfinylphenyl)methylthio]-5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole

Analogously to example 12 from 2-hydroxy-5-methylthiobenzyl alcohol and5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole-2-thione in glacial aceticacid/conc. hydrochloric acid/H₂O₂:

¹H NMR ([D₃]MeOD): δ(ppm)=8.41 (m, 2H, AA′, 4-Pyr); 7.47-7.41 (m, 6H,BB′ 4-Pyr, 4-F—Ph, C2′-H, C4′-H); 7.21-7.11 (m, 2H, 4-F—Ph); 6.96 (d,1H, J=8.2 Hz, C5′-H); 4.33 (s, 2H, methylene); 2.60 (s, 3H, methyl);

¹³C NMR ([D₃]MeOD): δ(ppm)=166.87; 161.95; 160.11; 150.28; 143.07;134.91; 132.01; 131.85; 128.58; 127.73; 127.72; 126.37; 122.99; 117.58;117.22; 116.78; 43.45; 34.57

IR (KBr): 1/λ[cm⁻¹]=3410, 3129, 3069, 2991, 2913, 2360, 1603, 1571,1500, 1422, 1280, 1232, 1157, 1078, 1031, 1003, 826, 697, 586

Activity Tests

Test System for Determining the Inhibition of 5-lipoxygenase (5-LO)

The source used for the 5-lipoxygenase is human granulocytes. Bystimulation with calcium ionophore A 23187, LTB₄ (leukotriene B₄) isformed from endogenous arachidonic acid. The granulocytes are isolatedand the enzyme reaction is carried out according to known processes (seeArch. Pharm. Pharm. Med. Chem. 330, 307-312 (1997)).

The blood protected from clotting by heparin is centrifuged on adiscontinuous Percoll® gradient and the granulocyte layer is removed bypipette. After lysis of the erythrocytes, the granulocytes are washed anumber of times and then adjusted to a specific cell count. The enzymereaction is then started in the presence or absence of the testsubstance after addition of Ca²⁺ using calcium ionophore A 23187. Thesynthesis of the leukotrienes is stopped after 1.5 minutes. The samplesare centrifuged off and the supernatant is diluted. LTB₄ is determinedquantitatively by means of ELISA.

Test System for Determining the Inhibition of Cyclooxygenase-1 (COX-1)

In this test system, the amount of prostaglandin E₂ formed by humanplatelets after addition of calcium ionophore is determined by means ofELISA. The platelets are obtained here after centrifugation on adiscontinuous Percoll® gradient. The enzyme reaction and thedetermination of the metabolites formed are in principle carried out asin the determination of the inhibition of 5-lipoxygenase. Differencesexist with respect to the incubation time. Furthermore, the addition ofa thromboxane synthase inhibitor is necessary (see Arch. Pharm. Pharm.Med. Chem. 330, 307-312 (1997)).

Test System for Determining the Inhibition of Cyclooxygenase-2 (COX-2)

COX-2 (from sheep placenta) is preincubated with test substance for 10min at 4° C., then stimulated with arachidonic acid (5 μm) at 25° C. for10 min. The reference used is diclofenac (IC₅₀ (COX-2)=3.0 10⁻⁶ M).Determination is carried out 3 dilutions (10⁻⁷, 10⁻⁶, 10⁻⁵ molar). ThePGE₂ concentrations are quantified by means of ELISA (see Mitchell J. A.et al. Proc. Nat. Acad. Sci 90: 11693-11697 (1993)).

Test System for Determining the Inhibition of LPS-stimulated CytokineSecretion (TNF-α, IL-1β)

Human PBMC (peripheral blood mononuclear cells) are preincubated withtest substance for 5 min at 37° C., then stimulated with LPS (1 μg/ml)for 24 h at 37° C. The cytokines TNF-α, IL-1β, IL-6 and IL-8 areDetermined by means of ELISA (see Blood 75, 40-47 (1990)).

Test System for Determining the Inhibition of LPS-stimulated CytokineSecretion (TNF-α, IL-1β) in Whole Blood

Fresh, human whole blood from healthy donors is preincubated with testsubstance for 25 min at 37° C. The cells are stimulated with LPS (1μg/ml) for 4 h at 37° C. In the plasma supernatant which is isolated bycentrifugation, the cytokines TNF-α, IL-1β, IL-6 and IL-8 are quantifiedby means of ELISA (see Inflamm. Res. 44, 269-274 (1995)).

The results of the activity tests carried out using the test systemsdescribed above are summarized in tables 1 and 2. The tables show theinfluence of the compounds according to the invention of examples 1-7,9, 10, 12 and 16 on the release of the inflammatory mediators COX-1,COX-2, 5-LO, TNF-α and IL-1β (table 1) in comparison with the referencesubstances A and B (table 2), whose structure is likewise indicated intable 2.

The reference substances A and B were synthesized according to theprocedure described in WO 93/14081 (p. 35, examples 19 and 20 therein).

TABLE 1 Influence of the test compounds on the release of inflammatorymediators (IC₅₀ values in μmol): Example Structure COX-1 COX-2 5-LO TNFαIL-1β

1

3.4 6.1 0.065 PBMC: 10.0 Whole blood method: 30 PBMC: >100.0 Whole bloodmethod: 30 2

— 6.3 10 PBMC: 6.8 Whole blood method: 16 PBMC: 2.3 Whole blood method:2.9 3

— — 0.8 PBMC: 4.0 Whole blood method: 19 PBMC: >100 Whole blood method:1.2 4

2.2 7.0 0.085 PBMC: 3.3 PBMC: 9.3 5

 0.038 10.0  2.8 PBMC: 3.1 PBMC: 18 6

6.5 3.0 <0.01 PBMC: 6.0 PBMC: 58 7

— — — PBMC: 14 PBMC: 21 9

Whole blood method: 24 Whole blood method: 1.9 10

Whole blood method: 48 Whole blood method: 4.0 12

Whole blood method: 9.0 Whole blood method: 12.1 16

PBMC: 4.2 Whole blood method: 76 PBMC: 0.64 Whole blood method: 13

TABLE 2 Influence of the reference substances on the release ofinflammatory mediators (IC₅₀ values in μmol) Reference A SB 203580

PBMC: 1.4 Whole blood method: 1.8 PBMC: 0.1 Whole blood method: 0.3Reference B

PBMC: 7.5

What is claimed is:
 1. A compound of formula I

in which Ar is a phenyl radical which can optionally be substituted byone or more substituents, selected from halogen, C₁₋₄-alkyl, C₁₋₄-alkoxyand C₁₋₄-alkylthio; Het is a pyridyl which can optionally be substitutedby one or more substituents selected from halogen, amino,C₁₋₄-alkylamino, C₁₋₄-alkyl, hydroxyl, C₁₋₄-alkoxy or C₁₋₄-alkylthio; Ais a straight-chain or branched, saturated or unsaturated alkylene chainhaving up to 6 carbon atoms; R¹ is C₁₋₄-alkylthio, C₁₋₄-alkylsulfinyl,C₁₋₄-alkylsulfonyl, or sulfonamido; R² is halogen, C₁₋₄-alkyl, hydroxyl,C₁₋₄-alkoxy, C₁₋₄-alkoxycarbonyl, sulfonamido, carboxyl, nitro oraminocarbonyl; n is 1 or 2; and m is 0 to 2, or a pharmaceuticallytolerable salt thereof.
 2. A compound as claimed in claim 1, in whichthe heteroaromatic radical Het is a 4-pyridyl, or a 3-amino-4-pyridylgroup.
 3. A compound as claimed in claim 1, in which the phenyl radicalAr is substituted by one or more substituents selected from fluorine,chlorine, bromine, C₁₋₄-alkyl, C₁₋₄-alkoxy, or C₁₋₄-alkylthio.
 4. Acompound as claimed in claim 3, in which the substituent or thesubstituents for Ar are selected from fluorine, chlorine, methoxy andmethylthio.
 5. A compound as claimed in claim 4, in which the phenylradical Ar is a 4-fluorophenyl group.
 6. A compound as claimed in claim1, in which n is
 1. 7. A compound as claimed in claim 1, in which thephenyl radical Ar is a 4-fluorophenyl group, the heteroaromatic radicalHet is a 4-pyridyl group, A is methylene or ethylene and n is
 1. 8. Acompound as claimed in claim 1, selected from the group consisting of:5-(4-fluorophenyl)-2-[(4-methylsulfanylphenyl)methylsulfanyl]-4-pyridylimidazole;5-(4-fluorophenyl)-2-[(4-methylsulfinylphenyl)methylsulfanyl]-4-pyridylimidazole;5-(4-fluorophenyl)-2-[(4-methylsulfonylphenyl)methylsulfanyl]-4-pyridylimidazole;2-[(4-aminosulfonylphenyl)methylsulfanyl]-5-(4-fluorophenyl)-4-pyridylimidazole;2-[2-(4-aminosulfonylphenyl)ethylsulfanyl]-5-(4-fluorophenyl)-4-pyridylimidazole;5-(4-fluorophenyl)-2-[2-(4-methylsulfanylphenyl)ethylsulfanyl]-4-pyridylimidazole;5-(4-fluorophenyl)-2-[2-(4-methylsulfonylphenyl)ethylsulfanyl]-4-pyridylimidazole;5-(4-fluorophenyl)-2-[(3-methylsulfanylphenyl)methylsulfanyl]-4-pyridylimidazole;5-(4-fluorophenyl)-2-[(2-methylsulfanylphenyl)methylsulfanyl]-4-pyridylimidazole;5-(4-fluorophenyl)-2-[(3-methylsulfinylphenyl)methylsulfanyl]-4-pyridylimidazole;5-(4-fluorophenyl)-2-[(2-methylsulfinylphenyl)methylsulfanyl]-4-pyridylimidazole;5-(4-fluorophenyl)-2-[(4-hydroxy-3-methylsulfanylphenyl)methylsulfanyl]-4-pyridylimidazole;5-(4-fluorophenyl)-2-[(4-hydroxy-3-methylsulfanylphenyl)methylsulfanyl]-4-pyridylimidazole;2-[(5-chloro-2-hydroxy-3-methylsulfanylphenyl)methylsulfanyl]-5-(4-fluorophenyl)-4-pyridylimidazole;and2-[(5-chloro-2-hydroxy-3-methylsulfinylphenyl)methylsulfanyl]-5-(4-fluorophenyl)-4-pyridylimidazole.9. A process for the preparation of a compound of formula I as claimedin claim 1, in which an imidazole-2-thione of formula II

in which Ar and Het are as defined in claim 1, is reacted with acompound of formula III

in which A, R¹, R², n and m are as in claim 1 and X is a leaving group,to give a compound of formula I or a pharmaceutically tolerable saltthereof.
 10. A pharmaceutical composition comprising a pharmaceuticallyeffective amount of a compound of formula I as claimed in claim 1 or apharmaceutically tolerable salt thereof and a pharmaceuticallyacceptable carrier.
 11. A method for treating inflamation comprisingadministering to a subject in need thereof, a pharmaceutically effectiveamount of a compound according to claim
 1. 12. A method for inhibitingrelease of cytokines comprising administering to a subject in needthereof, a pharmaceutically effective amount of a compound according toclaim
 1. 13. A method for treating a disease selected from the groupconsisting of rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gout, toxic shock syndrome, sepsis, adult respiratorydistress syndrome (ARDS), inflammatory bowel disease (IBD), cachexia,ulcerative colitis, Crohn's disease, inflammatory, skin diseases andpsoriatic arthritis, comprising administering to a subject in needtherof suffering from said disease, a pharmaceutically effective amountof a compound according to claim
 1. 14. The compound2-[(4-aminosulfonylphenyl)-methylthio]-5-(4-fluorophenyl)-4-pyridyl)imidazole.